What Is Treatment-Resistant Depression?

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If you have tried three or four different single medications for your depression over a period of months (or even years) and have not gotten relief from your symptoms, then your depression is classified as treatment-resistant or hard to treat. Treatment-resistant depression is not uncommon. Patients receiving single antidepressant treatment, or monotherapy, may be partially or totally resistant to treatment in up to 30 percent of cases.

But remember that depression – even treatment-resistant depression – is treatable. If your current depression treatment is not working, there probably is another approach that will yield results. The important thing is to actively work with your doctor or mental health professional to set goals for treatment and identify the approach or approaches that work for you.

What Causes Treatment-Resistant Depression?

A number of factors can cause treatment-resistant depression, such as:

Noncompliance with your medication regimen. If you skip doses and aren't conscientious about taking your medication, it will be less effective.

Depression that was more severe then your doctor thought. The more severe your depression, the longer episodes are likely to last and the more resistant to treatment it is likely to be.

Your medication was not prescribed in a high enough dosage or maintained long enough to have an effect.

Your initial diagnosis was wrong. Sometimes bipolar disorder (also called manic-depressive disorder) is misdiagnosed as depression if the depression phase of the disorder is more pronounced than the manic phase.

There were other medical conditions that caused or exacerbated your depression. Menopause, thyroid disorders, anemia, heart problems and chronic pain are some of the conditions that can worsen depression symptoms.

An unhealthy lifestyle characterized by a poor diet, insufficient exercise or substance abuse.

Taking a medication that conflicts with your depression medication, such as certain beta-blockers or certain Parkinson's disease medications.

Continuing stress and personal issues in your life. Medication may be less effective if you have continual stress because of unresolved issues in your life, such as strained personal, marital or family relationships, the death of a loved one, or work or financial pressures.

Get Re-evaluated for Depression and Consider Treatment Changes

Start by telling your doctor that your symptoms are not getting any better. He or she may:

Review your medical and family history and your symptoms to make sure your diagnosis is correct.

Carry out tests for other medical conditions that may be exacerbating or mimicking depression.

Discuss your life situation with you. You need to be honest about the stresses you face, even embarrassing ones such as sexual problems or alcohol or substance abuse.

Order cytochrome P450 (CYP450) genotyping tests to check for specific genes that affect how your body responds to anti-depressants. This test might help determine if you are resistant to your current medication.

It is possible that the review may not disclose any obvious reason why your treatment is not working. Consequently, your doctor may recommend – or you can request – a referral to a mental health specialist, such as a psychiatrist, psychologist or psychotherapist, if you're not already seeing one, for other forms of medical and nonmedical therapy.

The Art and Science of Choosing Depression Therapies

Prescribing medications for depression is part science and part art, and finding an effective medical approach may require some trial and error. A psychiatrist, especially one trained in psychopharmacology, will have broader experience prescribing medications and evaluating their effectiveness than will many family physicians. Among the approaches that may be considered:

Increasing the dosage of or length of time on medications that have previously been ineffective. Some studies have suggested that dosages or treatment times in excess of the recommended guidelines can successfully treat treatment-resistant depression. The general guideline has been to try a medication for at least six weeks, but new studies recommend continuing on the initial anti-depressant, often a serotonin reuptake inhibitor (SSRI; some examples are Prozac [fluoxetine], Zoloft [sertraline], Luvox [fluvoxamine] and Paxil [paroxetine]), for 12 to 14 weeks before trying something else.

Switching medications. If you haven''t already tried this, your doctor may first try switching you to another anti-depressant in the same class, for example, switching the SSRI Celexa (citalopram) to the SSRI Zoloft (sertraline). Alternatively, you might be switched from an SSRI to a serotonin and norepinephrine reuptake inhibitor (SNRI; some examples are Cymbalta [duloxetine hydrochloride], Effexor [venlafaxine] and Serzone [nefazodone]) or some other class of anti-depressant.

Augmenting the antidepressant with another psychiatric medication. The psychiatric medications often used in this way include mood stabilizers, anti-seizure medications, anti-psychotics, stimulants and beta-blockers, any of which may affect other neurotransmitter chemicals and thus heighten the effect of the anti-depressant. A drawback is that there may be new side effects and/or frequent blood tests may be needed depending on the medications used.

Combining anti-depressants. This entails using different classes of antidepressants in combination to achieve greater effect, such as an SSRI and an anti-depressant known as a norepinephrine and dopamine reuptake inhibitor (NDRI; some examples are Wellbutrin and Zyban [bupropion]). Another combination might be an SSRI and an older tricyclic anti-depressant (TCA; some examples are Tofranil [imipramine], Elavil [amitriptyline], Pamelor [nortriptyline] and Norpramin [desipramine]). The combination approach may be effective because it targets multiple brain chemicals at the same time, including dopamine, serotonin and norepinephrine.

Stepped-Up Treatment for Depression: The STAR*D Study

Treatment-resistant depression is so common that the National Institute of Mental Health (NIMH) conducted an extensive study of alternatives for stepped-up treatment. The 2006 Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study involving 1,439 patients looked at switch, augmentation and combination options at each of four levels of progressive treatment. Patients who failed to achieve symptom relief at one level were moved to the next level. The levels were:

Level 1: A single anti-depressant (monotherapy) with the SSRI Celexa (citalopram) for up to 14 weeks.

Level 2: Patients were presented with seven different treatment options, but most chose to switch to one of three different medications (51 percent) or to augment the Celexa with one of the two augmenting medications (39 percent). The "switch" medications were the SSRI Zoloft (sertraline), a non-SSRI, Wellbutrin SR (bupropion-SR) or Effexor (venlafaxine-XR), an agent that targets the neurotransmitters serotonin and norepinephrine. The "augmenting" medications were either Wellbutrin SR or BuSpar (buspirone), which enhances the action of an SSRI.

Level 3: Patients had the option of switching to a different medication or adding another medication, either the mood stabilizer lithium or the thyroid medication Cytomel (triiodothyronine, or T3). Both have been shown to boost the effectiveness of anti-depressant medications.

Level 4: Patients were switched to one of two treatments: A combination of Effexor-XR (venlafaxine-XR) and Remeron (mirtazapine) or Parnate (tranylcypromine). Parnate is a monoamine oxidase inhibitor (MAOI), an older class of anti-depressant that can dangerously interact with certain foods or medications. Therefore, patients who chose Parnate adhered to dietary restrictions.

How the STAR*D Treatment Approach Worked on Depression

This is how patients with depression fared using the stepped-up treatment approach in the STAR*D study:

Level 2: One-fourth of patients who switched medications were symptom free within 14 weeks; one-third of those who followed the augmentation strategy were symptom free at 14 weeks.

Level 3: One-fifth of patients who took one of the new combinations for an average of nine weeks became symptom-free.

Level 4: One-tenth of patients who took the new medications for an average of nine weeks became symptom-free.

Over the course of all four levels, about 70 percent of those who continued in the study were eventually free of symptoms of depression.

Nondrug Treatments for Severe Depression

Some of these treatments are controversial and some are experimental. But if you have not been able to get symptom relief otherwise, you may want to discuss them with your doctor. They include:

Electroconvulsive therapy (ECT). Also called "electroshock therapy", this treatment entails sending an electric current through the brain to provoke a seizure. Although the older, harsher versions of this treatment fell into disfavor, the method of ECT used today can safely and painlessly bring effective relief of depression symptoms for some people for whom other treatments have not worked.

Vagus nerve stimulation (VNS). Approved by the FDA in 2005 for severe treatment-resistant depression, VNS uses a surgically implanted pulse generator as a kind of "pacemaker" to send electrical current through the vagus nerve to mood centers in the brain.

Transcranial magnetic stimulation (TMS). TMS is an experimental therapy that uses a large electromagnetic coil held against the forehead to excite neurons in the brain by producing a mild electrical current.

Deep brain stimulation (DBS). This is another experimental treatment for depression in which electrodes are surgically implanted in the brain to direct electrical impulses to targeted brain regions.

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